1. Field of the Invention
The present invention relates to a composition comprising Melissa leaf extract having inhibitory activity on angiogenesis and matrix metalloproteinase. The present invention further relates to composition comprising Melissa leaf extract as active ingredient, which can be used as pharmaceuticals, food or cosmetics for treatment or prevention of angiogenesis- and/or MMP-dependent diseases.
2. General Background and State of the Art
Melissa (Melissa officinalis), a plant in a Labiatae family, is also called lemon balm, balm, or dropsy plant as common and folk names.
Some of the key constituents of Melissa officinalis extract are volatile oils (geranial, neral, citronellal, linalool, geraniol, geranylacetate, methyl citronellate, trans-beta-ocimene, germacren, eugenol), caffeic acid derivatives, flavonoids, triterpenes, catechins and tannins. Rosmarinic acid, a derivative of caffeic acid, is the most abundant component (about 4.7%) of the Melissa leaf extract, which is known to have anti-inflammatory activity.
Melissa is edible and medicinal. Fresh leaves can be added to salad and used to make sauces for fish, poultry and pork. Dried or fresh the whole plant is used to make cool refreshing drinks or warm relaxing teas, which is good for fevers, colds, and headache. As an alternative medicine, it is applied for calming nerves, relieving menstrual cramps, insomnia, depression, hyperthyroidism, upset stomach, and colic in babies. It is antibacterial, antispasmodic, antiviral, carminative, diaphoretic, digestive, emmenagogue, febrifuge, sedative, and tonic. Melissa leaf extract is also considered a blood circulation activator, which helps in dilation of peripheral blood vessels. Fresh crushed leaves are applied to wounds and insect bites. The oil from Melissa is often added to skin preparations and perfumes. The essential oil is also used in aromatherapy (Cohen R A, Kucera L S, Herrmann E C Jr., Proc Soc Exp Biol Med 117, 431-434, 1964; Kucera L S, Cohen R A and Herrmann E C Jr, Ann. NY Acad Sci 130, 474-82, 1965).
Angiogenesis is the process of generating new capillary blood vessels. This results from activated proliferation of pre-existing endothelial cells. Neovascularization is tightly regulated, and activation occurs only during embryogenic development, tissue remodeling, wound healing and periodic cycles of corpus luteum development (Folkman and Cotran, Relation of vascular proliferation to tumor growth, Int Rev Exp Pathol 16 207-248, 1976).
Endothelial cells grow very slowly as compared with other types of cells in the body. However, if the proliferation of these cells is induced by the failure of regulation of angiogenesis, some pathological status is developed (Timar, J Pathol Oncol Res 6, 85-94, 2001). Pathological angiogenesis is involved in many diseases. For example, cardiovascular diseases such as angioma, angiofibroma, vascular deformity, atherosclerosis, synechia and edemic sclerosis; and opthalmological diseases such as neovascularization after cornea implantation, neovascular glaucoma, diabetic retinopathy, angiogenic corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasias, and granular conjunctivitis are related to angiogenesis. Chronic inflammatory diseases such as arthritis, dermatological disease such as psoriasis, telangiectasis, pyogenic granuloma, seborrheic dermatitis and acne are also angiogenesis-dependent.
In particular, angiogenesis is essential to metastasis and growth of cancer (D'Amato R J and Adamis A P, Ophthalmol 102, 1261-1262, 1995; Arbiser J L, J Am Acad Derm 34, 486-497, 1996; O'Brien K. D. et al. Circulation 93, 672-682, 1996; Hanahan D and Folkman J, Cell 86, 353-364, 1996). New blood vessels provide not only nutrients and oxygen to fast-growing cancer cells, but also ways of entering the blood stream resulting in metastasis (Polverini P. J., Critical Reviews in Oral Biology, 6, 230-247, 1995). Currently, a large variety of chemotherapy and immunotherapy are applied in the treatment of cancer, but the efficacy of the therapies is limited and nothing can successfully extend the life of cancer patients, due to the lack of anti-metastasis effects.
Arthritis, a well-known inflammatory disease, is initiated as an autoimmune disease. However, the growth of vascular endothelial cell in the synovial cavity is activated by the inflammatory cytokines, which finally destroy cartilage in the articulation (Kocb A E, Polverini P J and Lcibovich S J, Arth Rheum 29, 471-479, 1986; Stupack D G, Storgard C M and Cheresh D A, Braz J Med Biol Rcs 32, 578-581, 1999; Koch A E, Arthritis Rheum 41, 951-962, 1998).
Many people are losing their eyesight all over the world because of various ocular diseases. Many patients become blind due to the infiltration of the capillary blood cells into the vitreous humor (Jeffrey M I and Takayuki A, J Clin Invest 103, 1231-1236, 1999).
Psoriasis is caused by extremely active proliferation of skin cells. Fast-growing cells requires sufficient blood supply, and angiogenesis is abnormally induced in psoriasis (Folkman J., J Invest Dermatol 59, 40-48, 1972).
As mentioned above, angiogenesis is closely related to initiation and progression of many diseases. Therefore, inhibitors of angiogenesis can be the good candidates for the treatment of those diseases. Many efforts have been made toward the development of angiogenesis inhibitors in order to prevent and/or treat those diseases.
Since the individual cells that make up even a single tumor vessel vary widely, the effectiveness of cancer treatments can be improved with various types of anti-angiogenic therapy. It is desirable to prepare a cocktail of several angiogenesis inhibitors for optimal anti-angiogenic therapy.
One of the major events for inducing angiogenesis is a breakdown of the extracellular matrix before the formation of the capillary blood vessels. The most important enzyme of matrix degradation is matrix metalloproteinase (MMP), a family of over 20 enzymes. MMPs are endopeptidase, which degrade or proteolyze the components of the extracellular matrix such as collagen, proteoglycan, and gelatin, and are classified into four groups: collagenase, gelatinase, stromelysin, and membrane-type MMP. Many enzymes in the MMP family have substrate specificity. The expression of MMP is induced under various physiological circumstances when remodeling of an extracellular matrix is required (Curry T E Jr, Osteen K G, Biol Repord 64, 1285-1296, 2001; Damjanovske S, Amano T, Li Q, Ueda S, Shi Y B, Ishizuya-Oka A, Ann NY Acad Sci 926, 180-191, 2000; Ravanti L, Kahari V M, Int J Mol Med 6, 391-407 2000).
Increased expression or activation of MMPs is observed in many pathological states, such as atherosclerosis, Alzheimer's disease, skin aging, wrinkle, arthritis, corneal ulcer, proteinuria, abdominal aortic aneurysm, regressive cartilage loss, myelinated nerve loss, liver fibrosis, nephroglomerular disease, germinal membrane ruptures, inflammatory bowel disease, gingivitis/periodontitis, senile macular degeneration, retinopathy, Sjogren syndrome, myopia, rejection of cornea implantation, angiogenesis and cancer metastasis. (Woessner Jr., Annals NY Acad Sci, 732, 11-21, 1994; Warner et al., Am J Pathol, 158, 2139-44, 2001; Stetler-Stevenson, Surg Oncol Clin N Am, 10, 383-92, 2001)
For example, stromelysins are known to be the major enzymes for disruption of cartilage (Murphy, G. et al., Biochem J, 248, 265-268, 1987). Collagenases, gelatinases and stromelysins are responsible for the degradation of the extracellular matrix in many types of retinopathies (Bruns, F. R. et al., Invest Opthalmol and Visual Sci, 32, 1569-1575, 1989). Collagenases and stromelysins are identified in fibroblast from gingiva in inflammation, and the activity of the enzyme is dependent on the degree of inflammation (Beeley, N. R. A. et al., supra; Overall, C. M. et al., J Periodontal Res, 22, 81-88, 1987).
Recent reports have also shown that MMP-1 activity is highly induced in Alzheimer's disease, and MMP-1 and MMP-3 are involved in the pathophysiology of the disease (Leake A, Morris C M, & Whateley, J Neurosci Lett 291, 201-3, 2000; Yoshiyama Y, Asahina M, & Hattori T, Acta Neuropathol (berl), 99, 91-5, 2000).
MMPs are also responsible in solar UV radiation-induced skin damage, affecting skin tone and resiliency leading to premature aging. The symptoms of which include leathery texture, wrinkles, mottled pigmentation, laxity and sallowness. Therefore, MMP inhibitors could be included in cosmetics for anti-photoaging or anti-wrinkle agent (Hase T, Shinata K, Murase T, Tokimitsu I, Hattori M, Takimoto R, Tsuboi R and Ogawa H, Br J Dermatol 142, 267-273, 2000; Fisher G J, Talwar H S, Lin J, Voorhees J J, Photochem Photobiol 69, 154-157, 1999).
Since inhibitors for MMP and angiogenesis can be applied for treatment of many diseases, development of angiogenesis inhibitor as new drugs is expected. Desirable inhibitors should not have toxic or adverse effect with good patient compliance because inhibitors need to be administered for a long time.